Malnutrition and loss of muscle mass (sarcopenia) are common in patients with end stage renal disease on hemodialysis and associated with increased mortality, impaired physical function, disability, and poor quality of life. Therefore, therapeutic interventions that can increase muscle mass and strength might improve physical function, general health perceptions, and reduce disability. Testosterone, when given in physiologic replacement doses, is an attractive anabolic intervention because it has been proven relatively safe, and effective in increasing muscle mass and strength in healthy hypogonadal men, older men with low testosterone levels, and HIV- infected men with weight loss. The primary objective of this study is to determine if testosterone replacement of men on maintenance hemodialysis who have low testosterone levels will increase their fat-free mass, muscle strength, physical function, and health-related quality of life. A second objective is to elucidate the mechanisms by which testosterone increases muscle mass. Men with end stage renal disease, 18-75 yrs of age, with serum testosterone less than 300 ng/dL, who are on maintenance hemodialysis, and free of acute illness, will be randomly assigned to receive either two placebo or two testosterone transdermal patches daily for 16 weeks. Two testosterone patches will nominally delivery 10 mg testosterone daily, and raise serum testosterone levels into the mid-range for healthy young men. Energy and protein intake, hemodialysis regimen, and erythropeitin dose will be standardized. The following outcomes will be measured at baseline and after 16 weeks: body composition by DEXA scan, deuterium oxide and sodium bromide dilution; thigh muscle volume by MRI scan; muscle performance by measurements of 5-repetition maximum strength, power, and endurance in the leg press exercise; and effort independent muscle performance by force:EMG relationship; physical function by stair climbing power, getting up from a chair, and walking speed; self-reported disability and kidney disease quality of life by validated instruments; fractional synthesis rates of mixed skeletal muscle protein and myosin heavy chain during a primed, continuous infusion of L-[1,213C]-leucine. Total and free testosterone and dihydrotestosterone levels will be measured as markers of androgen bioavailability, and LH, FSH, and SHBG as markers of androgen action. For safety, we will follow hemoglobin/hematocrit, AST and ALT, PSA, plasma lipids, apolipoproteins, and lipoprotein particles, and insulin sensitivity by the modified Bergman Minimal Model. Muscle biopsies will also be used for measurements of myostatin, IGF-1, and IGFBP-4 mRNA and protein concentrations by RT-PCR and Western blot analyses. A multi-disciplinary team of investigators, careful subject selection, access to a large patient pool, attention to potential confounding variables such as dialysis intensity, erythropoeitin dose, dietary intake and exercise stimulus, and power and effect size, and state-of-the-art methods should maximize the chances of detecting treatment effects and elucidating the mechanism of androgen action. Therefore, if successful, this study should help identify a therapeutic intervention that might improve physical function and reduce disability in men with end stage renal disease.